Cardiovascular disease is the leading cause of death among women in the United States. Postmenopausal women are most susceptible to this deadly disease. The dramatic increase in cardiovascular mortality rate among postmenopausal women is largely due to deterioration in arterial compliance associated with the reduction in nitric oxide (NO) production during menopause. Estrogen replacement therapy reverses the deterioration process by stimulating NO production but introduces increased risk of breast cancer. Isoflavones, which have chemical structures similar to estradiol but possess anti-cancer properties, are found in abundance in soybeans. Our preliminary data showed that diastolic blood pressure was reduced by 12% and urinary nitrate excretion was increased by 33% in postmenopausal women receiving soy isoflavone therapy. We are not aware of any studies confirming the stimulatory effect of soy isoflavones on NO production. Therefore, we propose to study 56 healthy postmenopausal women with high-normal blood pressure, using a double-blind, randomized, placebo-controlled design, to confirm the stimulatory effect of soy isoflavone therapy on NO production and reduction in blood pressure and vascular resistance. We propose to use a primed, 6-h constant infusion of L-guanidino-15N2]arginine to measure the NO production, both before and after 6 weeks of isoflavone or placebo therapy. Gas chromatography-mass spectrometry will be used to measure the isotopic abundance of L-guanidino-'5N2]arginine and the products of the arginine-NO synthase pathway in the blood and urine samples. To monitor the hemodynamic effects of isoflavone therapy, 24-h ambulatory blood pressure, arterial compliance, and basal and post-ischemic forearm blood flow will be measured, before and after 6 weeks of isoflavone or placebo therapy. Plasma isoflavone concentrations, an index of subject compliance, will be measured by HPLC-mass spectrometry. The sample size will allow us to detect differences of 0.3 % pool/h in NO production, 0.2 mmol/d in urinary nitrate excretion, 1 mmHg/mL/min in arterial compliance, 3 mL.min-1.100 mL forearm-1 in forearm bloodflow, and8 mmHg in diastolic blood pressure.